Chaturvedi A, Herbst L, Pusch S, Klett L, Goparaju R, Stichel D, Kaulfuss S, Panknin O, Zimmermann K, Toschi L, Neuhaus R, Haegebarth A, Rehwinkel H, Hess-Stumpp H, Bauser M, Bochtler T, Struys E A, Sharma A, Bakkali A, Geffers R, Araujo-Cruz M M, Thol F, Gabdoulline R, Ganser A, Ho A D, von Deimling A, Rippe K, Heuser M, Krämer A
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ) and Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.
Leukemia. 2017 Oct;31(10):2020-2028. doi: 10.1038/leu.2017.46. Epub 2017 Jan 31.
Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are frequently found in several human cancer types including acute myeloid leukemia (AML) and lead to the production of high levels of the oncometabolite (R)-2-hydroxyglutarate (R-2HG). Here we report the characterization of BAY1436032, a novel pan-mutant IDH1 inhibitor, both in vitro and in vivo. BAY1436032 specifically inhibits R-2HG production and colony growth, and induces myeloid differentiation of AML cells carrying IDH1R132H, IDH1R132C, IDH1R132G, IDH1R132L and IDH1R132S mutations. In addition, the compound impacts on DNA methylation and attenuates histone hypermethylation. Oral administration of BAY1436032 led to leukemic blast clearance, myeloid differentiation, depletion of leukemic stem cells and prolonged survival in two independent patient-derived xenograft IDH1 mutant AML mouse models. Together, BAY1436032 is highly effective against all major types of IDH1 mutant AML.
异柠檬酸脱氢酶1（IDH1）的新形态突变常见于包括急性髓系白血病（AML）在内的多种人类癌症类型中，并导致高水平的致癌代谢物（R）-2-羟基戊二酸（R-2HG）的产生。在此，我们报告了新型泛突变IDH1抑制剂BAY1436032在体外和体内的特性。BAY1436032特异性抑制R-2HG的产生和集落生长，并诱导携带IDH1R132H、IDH1R132C、IDH1R132G、IDH1R132L和IDH1R132S突变的AML细胞发生髓系分化。此外，该化合物还影响DNA甲基化并减弱组蛋白高甲基化。在两个独立的患者来源的异种移植IDH1突变AML小鼠模型中，口服BAY1436032可导致白血病原始细胞清除、髓系分化、白血病干细胞耗竭并延长生存期。总之，BAY1436032对所有主要类型的IDH1突变AML均具有高效性。
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